This invention relates to pharmacology, and to medical treatments for bronchial asthma.
Bronchial asthma is a common disease that involves narrowing of the airways, in a manner which renders it difficult for a person to breathe. As used herein, all references to "asthma" refer to bronchial asthma, which is distinct from a different problem known to physicians as cardiac asthma.
Asthma is a widespread problem (estimated to affect up to 10 to 20% of the population, at varying levels of severity), and a huge amount of information is available in the scientific and medical literature and in the popular press, on the physiological and cellular events and mediators that are involved in asthma, and on drug treatments that have been studied in an effort to help control it. A partial listing of review articles published just in the first half of 1997 include Everard 1997, Floreani et al 1997, Nourshargh 1997, Higgs 1997, Saint-Remy 1997, Bentley et al 1997, Jacoby 1997, Spector 1997, Corrigan et al 1997, and Barnes et al 1997 (complete citations to books and articles are provided below, immediately before the claims). The following is a very brief overview of certain relevant interactions that contribute to asthma attacks; more information can be obtained from any of the above cited articles, and numerous other such articles.
In asthma sufferers, narrowing of the airways is caused by an inflammatory reaction within the bronchial walls, involving various types of blood cells (including mast cells, eosinophils, and lymphocytes), muscle cells and other connective tissue cells, mediators, and cytokines. Typically, various allergens derived from organic material (such as pollen, house dust, feathers, animal hair, fungal spores, etc.) enter the bronchi, carried by the air that a person breathes in. These allergens stimulate formation of antibodies, mainly of the IgE class.
On subsequent exposure to the allergen, allergen-antibody interactions trigger a sequence of events which cause various cells (such as mast cells) in the bronchial walls to release mediators such as histamine (in general, "mediators" are pharmacologically-active molecules which are released by one or more types of cells, and which react with receptors on the surfaces of other types of cells, causing the receptor-bearing cells to initiate one or more responses). The intercellular mediators interact with cells such as bronchial smooth muscle cells, causing various cellular reactions that lead to bronchial constriction.
The histamine-mediated interaction between mast cells and bronchial smooth muscle cells is only one of the contributing mechanisms involved in asthma, and other types of cells and mediators are also involved in various chronic aspects of asthma. For example, the late phase of the asthmatic response is associated with an increase of nonspecific bronchial responsiveness, and with infiltration and accumulation of neutrophils, eosinophils, and other leukocytes in bronchial tissue. In particular, eosinophils that become involved in the asthmatic inflammatory process are believed to release certain types of toxic mediators which can injure the bronchial epithelium, causing further inflammation.
In asthmatic attacks, eosinophil proliferation is believed to be largely controlled (or at least aggravated) by cytokines IL-3 and IL-5, which are produced and released by certain types of activated T-lymphocytes. Therefore, there has been considerable interest in the role of T-lymphocytes in asthma attacks, because they have been implicated in the regulation of IgE production.
In animal studies, after exposure to asthma-producing allergens and to various drugs that are used to simulate asthma in animals, activated T-cells have been identified by an increased expression of IL-2 receptors on the T-cell surfaces, and by increased production and release of the interleukin mediators IL-3, IL-4, and IL-5. Further evidence supporting the importance of the eosinophils and T-cells in the pathogenesis of asthma comes from histological studies performed before and after treatment with inhalable anti-inflammatory steroids. Following several weeks of treatment with inhaled steroids such as beclomethasone dipropionate, significant reductions in the number of eosinophils and activated T-cells in the airways of asthmatic patients have been observed.
Additional evidence which casts light on the role of T-lymphocytes in asthma is provided in articles such as Alexander et al 1992, Calderon et al 1992, Fukuda et al 1995, and Corrigan et al 1996, all of which discuss the ability of cyclosporine A to reduce asthmatic symptoms. Cyclosporine A is a highly specific inhibitor which reduces the activation and proliferation of T-type lymphocyte cells, which play a major role in the immune system; it is the compound that is administered to recipients of transplanted organs, to prevent their bodies from rejecting the foreign tissue. Alexander et al conducted a 6-month double blind placebo-controlled trial of cyclosporine A, which demonstrated a clear beneficial effect on spirometric measures in patients with chronic severe asthma.
In Fukuda et al 1995, patients with corticosteroid-dependent chronic severe asthma were treated with cylosporin A (5 mg/kg/day initially) for 12 weeks. This treatment significantly increased the peak expiratory flow, and it reduced the airway's hyper-responsiveness to acetylcholine challenge. Fukuda and coworkers observed a significant reduction in T-lymphocytes bearing Il-2 receptors (a marker of T-cell activation) in the peripheral blood of these patients during the treatment.
Since cyclosporine is a highly selective and suppresses only T-type lymphocyte cells, these findings indicated that inhibition of T-lymphocytes activation in asthmatic patients, by cyclosporin A, reduced hyper-responsiveness of the airways, thereby improving expiratory air flow. However, these results are not especially promising or practicable for most asthma patients, since cyclosporin is a potent immunosuppressive compound that severely reduces a person's ability to resist infections. In general, cyclosporin is only administered to people who are facing life-threatening situations (such as recipients of transplanted organs, who will quickly die if their body rejects the foreign organ). It is not a medication that can be used frequently and safely by asthma sufferers.
One of the important features of asthma is that in many patients, it grows progressively worse, over the course of years. This arises from the fact that asthma involves allergic reactions that trigger the patient's immune system. As is well known, the immune system generally escalates its responses when it repeatedly encounters the same allergen, time after time. In asthma sufferers, the same allergens (such as pollen, house dust, feathers, animal hair, fungal spores, etc.) which provoked an initial attack are encountered again, and again, and again, because these types of allergens are so endemic, widespread, and unavoidable.
Therefore, many asthma sufferers are forced to gradually escalate their treatment regimens. Typically, when most patients suffer a first asthma attack that requires medical treatment, they try out one or more relatively mild, unaggressive drugs, in the hope that such drugs can provide adequate relief without imposing too much disruption or stress on the fragile tissues inside the lungs. Even if such relatively mild drugs give adequate relief for a period of months or years, a large fraction of the population of asthma sufferers suffer from increasingly severe attacks, as their immune systems become more and more hyper-sensitized to one or more types of allergens. Such patients must subsequently escalate their treatment regimens, and must begin using other drugs that are more potent, aggressive, and harsh, and which inflict higher levels of disruption and stress on the various types of immune cells and lung tissues involved in asthma attacks.
Despite the enormous amount of research on asthma and on drugs to help control asthma attacks in sufferers, there is no adequate and satisfactory treatment for asthma. Most sufferers must struggle with a variety of drugs, none of which are completely effective, and if their symptoms gradually grow worse (as often happens), they must periodically escalate their treatments to more powerful drugs, which inflict progressively greater demands, stress, and damage on their lungs.
Accordingly, one object of this invention is to disclose that a pharmacological agent which has not been recognized previously as an asthma treatment is, in fact, a useful and effective treatment for asthma attacks.
Another object of this invention is to disclose that fructose-1,6-diphosphate, a sugar-phosphate compound which is present in all living cells, can be a harmless and highly useful component of asthma therapy, with the potential for both (1) helping to treat asthma attacks, and (2) helping to reduce and prevent the gradual worsening of asthma attacks that occur in many sufferers, thereby allowing those patients to continue using, for as long as possible, asthma-control drugs that are relatively mild and benign, rather than the harsher and more potent drugs that would be required if their asthma attacks grow more severe over the course of months or years.
Another object of this invention is to disclose that fructose-1,6-diphosphate can be included as a component in various types of inhalable drug treatments for asthma sufferers, or as a stand-alone inhalable treatment for asthma sufferers.
These and other objects of the invention will become more apparent through the following summary, description, and examples.